• 食源性肥胖(DIO)小鼠接受异基因造血干细胞移植(allo-HSCT)后,易发生肠道的急性移植物抗宿主病(GVHD),在接受allo-HSCT的患者中也有相似发现;
  • DIO小鼠中,肠道通透性、内毒素移位和促炎细胞因子生成均增加,其急性GVHD主要由供体的CD4+ T细胞介导;
  • DIO小鼠和高BMI患者中,肠道菌群多样性和梭菌科丰度均降低;
  • 预防性抗生素处理能保护DIO小鼠减轻肠道的急性GVHD,但对之后靶向皮肤的慢性GVHD无效。
Science Translational Medicine发表的一项最新研究表明,肥胖可加剧造血干细胞移植后的急性移植物抗宿主病,增加死亡率。进一步分析表明,肥胖相关肠道菌群可能在其中起作用;在移植前进行抗生素处理,能对肥胖小鼠有部分保护作用。

Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation



2020-11-25, Article

Abstract & Authors:展开

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice with diet-induced obesity (DIO). These animals exhibited increased gut permeability, endotoxin translocation across the gut, and radiation-induced gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female DIO mouse recipients showed increased proinflammatory cytokine production and expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also exhibited decreased survival associated with acute severe gut GVHD. This rapid-onset, obesity-associated gut GVHD depended on donor CD4+ T cells and occurred even with a minor MHC mismatch between donor and recipient animals. Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from unrelated donors revealed that recipients with a high body mass index (BMI, >30) had reduced survival and higher serum ST2 concentrations compared with nonobese transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with a high BMI revealed reduced gut microbiota diversity and decreased Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse recipients from endotoxin translocation across the gut and increased inflammatory cytokine production, as well as gut pathology and mortality, but did not protect against later development of chronic skin GVHD. These results suggest that obesity-induced alterations of the gut microbiota may affect GVHD after allo-HSCT in DIO mice, which could be ameliorated by prophylactic antibiotic treatment.

First Authors:
Lam T Khuat

Correspondence Authors:
William J Murphy

All Authors:
Lam T Khuat,Catherine T Le,Chien-Chun Steven Pai,Robin R Shields-Cutler,Shernan G Holtan,Armin Rashidi,Sarah L Parker,Dan Knights,Jesus I Luna,Cordelia Dunai,Ziming Wang,Ian R Sturgill,Kevin M Stoffel,Alexander A Merleev,Shyam K More,Emanual Maverakis,Helen E Raybould,Mingyi Chen,Robert J Canter,Arta M Monjazeb,Maneesh Dave,James L M Ferrara,John E Levine,Dan L Longo,Mehrdad Abedi,Bruce R Blazar,William J Murphy